CN106854213B - Lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives and its preparation method and application - Google Patents

Lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives and its preparation method and application Download PDF

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CN106854213B
CN106854213B CN201611214564.0A CN201611214564A CN106854213B CN 106854213 B CN106854213 B CN 106854213B CN 201611214564 A CN201611214564 A CN 201611214564A CN 106854213 B CN106854213 B CN 106854213B
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lavo
formula
ofloxacin
thiourea derivatives
preparation
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CN106854213A (en
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李珂
李星
陈百泉
姜亚玲
胡国强
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Zhengzhou University of Industrial Technology
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Zhengzhou University of Industrial Technology
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract

The invention discloses a kind of lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives, general formula of the chemical structure is as follows：

Description

Lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives and preparation method thereof and Using
Technical field
The invention belongs to new drug discoveries and original new drug synthesis technical field, and in particular to a kind of lavo-ofloxacin aldehyde contracting 4- Arylamino thiourea derivatives, preparation method and its application in anti-tumor drug.
Background technique
New drug innovation originates from the discovery of primer, and is based on the split of advantage pharmacophore skeleton building primer molecule Most economical and effective strategy.By aldehydes or ketones and the thiosemicarbazone derivatives of thiosemicarbazide building because of it with macromolecular or Metal ion is also easy to produce complex or chelation and shows extensive pharmacological activity and be concerned.However, building contracting amino The aldehydes or ketones of thiocarbamide molecule are mostly the aldehyde and ketone of common benzene class or heteroaromatic class, and to quinoline aldehyde, especially fluoro quinolinone The (thiosemicarbazone) that aldehydes is formed has not been reported yet.On the other hand, quinoline advantage pharmacophore skeleton is not only important day Right product alkaloid, such as the pharmacophore bone of the important structural unit and antibacterial fluoroquinolone class drug of quinine and camptothecin Frame.Meanwhile fluoroquinolones increases its water solubility due to the presence of hydrophilic piperazinyl, improves bioavilability.Especially It is that action target spot-topoisomerase (TOPO) of fluoroquinolones is also the important function target spot of anti-tumor drug, can Anti-tumor activity is converted by its antibacterial activity.For this purpose, being that formoxyl forms corresponding fluorine quinoline by fluoquinolone C-3 converting carboxylate groups Then promise ketone C-3 aldehyde is condensed with thiosemicarbazide, and then realize the split between chinoline backbone and thiosemicarbazones pharmacophore, with Phase reaches the activity superposition between different structure pharmacophore, is therefrom found to have the fluoquinolone candidate compound of anti-tumor activity.
Summary of the invention
For this purpose, the object of the present invention is to provide a kind of lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives, tool There are antineoplastic action and effect, while additionally providing the system of above-mentioned lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives Preparation Method.
In order to achieve the goal above, the technical scheme adopted by the invention is that：A kind of lavo-ofloxacin aldehyde contracting 4- aryl ammonia Base thiourea derivatives, general formula of the chemical structure is as shown in formula I：
Wherein, substituent A r is phenyl ring, substituted benzene ring, pyridine ring, furan nucleus or thiphene ring.
Above-mentioned lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives, structural formula are specific as follows shown：
The preparation method of above-mentioned lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives, with the sand of oxygen fluorine shown in Formula II Star is prepared as a raw material, and specific preparation process is as follows：
1) lavo-ofloxacin shown in Formula II is subjected to hydrazinolysis with hydrazine hydrate and reacts lavo-ofloxacin shown in obtained formula III Hydrazides；
2) by lavo-ofloxacin hydrazides shown in formula III and the potassium ferricyanide in the ammonium hydroxide alkaline medium of chloroform normal-temperature reaction 8~12 hours, separate organic layer, and with saturated common salt water washing, anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, and formula IV is made Shown in intermediate lavo-ofloxacin aldehyde crude product, be directly used in the next step.
3) aromatic amine shown in Formula V and carbon disulfide are condensed as fragrant amino dithiocarbonic acid ammonium shown in Formula IV, then It is condensed to yield S- carboxymethyl fragrant amino dithiocarbonic acid ester sodium salt shown in Formula VII with sodium chloroacetate, is then occurred with hydrazine hydrate Substitution reaction, it is post-treated to obtain 4- fragrant amino thiourea derivatives shown in Formula VIII.
4) by 4- fragrant amino thiourea derivatives shown in lavo-ofloxacin aldehyde crude product shown in formula IV and Formula VIII in nothing Condensation reaction occurs for water-ethanol reflux, can be prepared by the contracting of lavo-ofloxacin aldehyde shown in Formulas I (4- virtue through processing after complete reaction Base) thiosemicarbazides analog derivative；
Wherein, substituent A r is phenyl ring, substituted benzene ring, pyridine ring, furan nucleus or thiphene ring.
The general step that is synthetically prepared of lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives shown in Formulas I is：It will 4- arylamino thiourea derivatives shown in lavo-ofloxacin aldehyde crude product and Formula VIII shown in formula IV return in dehydrated alcohol Stream reaction.Reaction terminates, and filters and collect the solid of generation, dry successively with dehydrated alcohol and distillation water washing.Crude product is used DMF- alcohol mixed solvent recrystallization, obtains Formulas I pale yellow crystals object.
As a further improvement, during preparation formula I, solvent used in back flow reaction is other than dehydrated alcohol, also It can choose at least one of methanol, normal propyl alcohol, isopropanol, isobutanol and n-butanol, wherein it is preferred that dehydrated alcohol.
Above-mentioned lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives application in preparation of anti-tumor drugs.Specifically , the anti-tumor drug is treatment liver cancer, cancer of pancreas or leukemia medicament.
Compared to the prior art, beneficial effects of the present invention：Lavo-ofloxacin aldehyde contracting 4- arylamino Thiourea of the present invention Split rational drug molecular design theory of the derivative based on pharmacophore, by chiral fluoroquinolone, imines schiff bases and thiocarbamide etc. Efficient combination between three kinds of different pharmacophores, and then Ofloxacin aldehyde contracting 4- arylamino thiourea derivatives are devised, it realizes The complementation of different structure pharmacophore and active superposition can be used as brand new to achieve synergistic and detoxifying effects Anti-tumor drug exploitation.
Specific embodiment
The technical scheme of the invention is described in detail through specific implementation examples.
In following embodiments, lavo-ofloxacin aldehyde crude product, is specifically obtained through following step shown in formula IV used：
1) lavo-ofloxacin shown in Formula II is subjected to hydrazinolysis with hydrazine hydrate and reacts lavo-ofloxacin shown in obtained formula III Hydrazides；Concrete operation step can refer to document, and (Hu Guoqiang waits synthesis and the antibacterial activity of quinolone C-3 acylhydrazone, Chinese pharmacy Magazine, 2010,45 (11):867-870.) method preparation；
2) by lavo-ofloxacin hydrazides shown in formula III and the potassium ferricyanide in the ammonium hydroxide alkaline medium of chloroform normal-temperature reaction 8~12 hours, separate organic layer, and with saturated common salt water washing, anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, and formula IV is made Shown in intermediate lavo-ofloxacin aldehyde crude product, be directly used in the next step.Concrete operation step is：By 10.0g (27.0mmol) Ofloxacin hydrazides is suspended in the mixed solution of 200 milliliters of chloroforms and 20 milliliters of concentrated ammonia liquors (concentration 22-25%) In, 120 milliliters of aqueous solution containing the potassium ferricyanide (38.0g, 115.0mmol) are slowly added dropwise in room temperature, and stirring at normal temperature is reacted to raw material Disappear (TLC detection, VChloroform：VMethanol=5:1).Separate organic layer, and with saturated common salt water washing, anhydrous sodium sulfate is dry, decompression Solvent is evaporated off, obtains lavo-ofloxacin aldehyde crude product shown in formula IV, it is spare.
In following embodiments, 4- fragrant amino thiourea derivatives, are specifically obtained through following step shown in Formula VIII used： Aromatic amine shown in Formula V and carbon disulfide are condensed as fragrant amino dithiocarbonic acid ammonium shown in Formula IV, then with sodium chloroacetate It is condensed to yield S- carboxymethyl fragrant amino dithiocarbonic acid ester sodium salt shown in Formula VII, substitution reaction, warp then occur with hydrazine hydrate Post-processing can obtain 4- fragrant amino thiourea derivatives shown in Formula VIII.Concrete operation step can refer to document (Hou Linyan, it is nitrogenous The synthesis of heterocyclic aryl thiosemicarbazones and antibacterial activity, master thesis, University Of Hebei, in 2011) method.
Embodiment 1
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- Phenylthiosemicarbazide (I-1), chemical structural formula are：
Ar i.e. in Formulas I is phenyl ring.
The preparation method of the compound is：Lavo-ofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 Milliliter), 4- phenyl thiosemicarbazide (0.6g, 3.6mmol) shown in Formula VIII is added, back flow reaction 12 hours, filters while hot, second Alcohol washs 2 times, and solid is successively washed with distilled water 2 times, dry, with DMF- ethyl alcohol (V:V=5:3) mixed solvent recrystallizes, and obtains Pale yellow crystals object formula (I-1), obtains product 0.63g, m.p.234~236 DEG C.1H NMR (400MHz, DMSO-d6)：11.76(s, 1H, CH=N), 9.95 (s, 1H, NH), 8.87 (s, 1H, 2-H), 8.45 (s, 1H, NH), 7.62~7.25 (m, 6H, Ph-H and 5-H), 4.61~4.34 (m, 3H, OCH2CH), 3.24 (t, 4H, piperazine-H), 2.45 (t, 4H, piperazine-H), 2.23 (s, 3H, N-CH3), 1.45 (d, 3H, CH3)；MS(m/z)：Calcd.for C25H27FN6O2S：494.60[M]+；Found： 495[M+H]+。
Embodiment 2
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- (4- aminomethyl phenyl) thiosemicarbazides (I-2), chemical structural formula are：
Ar i.e. in Formulas I is 4- aminomethyl phenyl.
The preparation method of the compound is：The crude product of lavo-ofloxacin aldehyde shown in formula IV (1.0g) is dissolved in dehydrated alcohol (30 millis Rise), be added Formula VIII shown in 4- (4- aminomethyl phenyl) thiosemicarbazides (0.6g, 3.3mmol), back flow reaction 10 hours, while hot Filtering, solid are successively used ethanol washing 2 times, are distilled water washing 2 times, dry, with DMF- ethyl alcohol (V:V=5:3) mixed solvent weight Crystallization, obtains pale yellow crystals object formula (I-2), obtains product 0.58g, m.p.227~229 DEG C.1H NMR (400MHz, DMSO-d6)： 11.77 (s, 1H, CH=N), 9.86 (s, 1H, NH), 8.91 (s, 1H, 2-H), 8.44 (s, 1H, NH), 8.25~7.46 (m, 5H, Ph-H and5-H), 4.63~4.35 (m, 3H, OCH2CH), 3.24 (t, 4H, piperazine-H), 2.42 (t, 4H, Piperazine-H), 2.36,2.23 (2s, 6H, Ph-CH3and N-CH3), 1.46 (d, 3H, CH3)；MS(m/z)： Calcd.for C26H29FN6O2S：508.62[M]+；Found：509[M+H]+。
Embodiment 3
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- (4- methoxyphenyl) thiosemicarbazides (I-2), chemical structural formula are：
Ar i.e. in Formulas I is 4- methoxyphenyl.
The preparation method of the compound is：Lavo-ofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 Milliliter), be added Formula VIII shown in 4- (4- methoxyphenyl) thiosemicarbazides (0.7g, 3.6mmol), back flow reaction 10 hours, It filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol (V:V=5:3) it mixes molten Agent recrystallization, obtains pale yellow crystals object formula (I-3), obtains product 0.65g, m.p.235~237 DEG C.1H NMR (400MHz, DMSO- d6)：11.75 (s, 1H, CH=N), 9.87 (s, 1H, NH), 8.87 (s, 1H, 2-H), 8.43 (s, 1H, NH), 7.48~6.95 (m, 5H, Ph-H and5-H), 4.58~4.33 (m, 3H, OCH2CH), 3.78 (s, 3H, OCH3), 3.24 (t, 4H, Piperazine-H), 2.45 (t, 4H, piperazine-H), 2.23 (s, 3H, N-CH3), 1.45 (d, 3H, CH3)；MS(m/z)： Calcd.for C26H29FN6O3S：524.62[M]+；Found：525[M+H]+。
Embodiment 4
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- (3- methoxyphenyl) thiosemicarbazides (I-4), chemical structural formula are：
Ar i.e. in Formulas I is 3- methoxyphenyl.
The preparation method of the compound is：The crude product of lavo-ofloxacin aldehyde shown in formula IV (1.0g) is dissolved in dehydrated alcohol (30 millis Rise), 4- (3- methoxyphenyl) thiosemicarbazides (0.7g, 3.6mmol) shown in Formula VIII is added, back flow reaction 11 hours, takes advantage of Heat filtering, solid are successively used ethanol washing 2 times, are distilled water washing 2 times, dry, with DMF- ethyl alcohol (V:V=5:3) mixed solvent Recrystallization, obtains pale yellow crystals object formula (I-4), obtains product 0.51g, m.p.218~220 DEG C.1H NMR (400MHz, DMSO- d6)：11.76 (s, 1H, CH=N), 9.87 (s, 1H, NH), 8.91 (s, 1H, 2-H), 8.42 (s, 1H, NH), 7.66~7.38 (m, 5H, Ph-H and5-H), 4.61~4.34 (m, 3H, OCH2CH), 3.76 (s, 3H, OCH3), 3.26 (t, 4H, Piperazine-H), 2.45 (t, 4H, piperazine-H), 2.23 (s, 3H, N-CH3), 1.46 (d, 3H, CH3)；MS(m/z)： Calcd.for C26H29FN6O3S：524.62[M]+；Found：525[M+H]+。
Embodiment 5
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- (3,4- Dimethoxyphenyl) thiosemicarbazides (I-5), chemical structural formula are：
Ar i.e. in Formulas I is 3,4- Dimethoxyphenyl.
The preparation method of the compound is：Lavo-ofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 Milliliter), 4- (3,4- Dimethoxyphenyl) thiosemicarbazides (0.8g, 3.5mmol) shown in Formula VIII is added, back flow reaction 12 is small When, it filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol (V:V=5:3) it mixes Solvent recrystallization, obtains pale yellow crystals object formula (I-5), obtains product 0.38g, m.p.212~214 DEG C.1H NMR (400MHz, DMSO-d6)：11.78 (s, 1H, CH=N), 9.93 (s, 1H, NH), 8.97 (s, 1H, 2-H), 8.44 (s, 1H, NH), 7.68~ 7.37 (m, 4H, Ph-H and 5-H), 4.62~4.34 (m, 3H, OCH2CH), 3.82,3.78 (2s, 6H, 2 × OCH3),3.25 (t, 4H, piperazine-H), 2.45 (t, 4H, piperazine-H), 2.23 (s, 3H, N-CH3), 1.46 (d, 3H, CH3)；MS (m/z)：Calcd.for C27H31FN6O4S：554.64[M]+；Found：555[M+H]+。
Embodiment 6
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- (4- fluorophenyl) thiosemicarbazides (I-6), chemical structural formula are：
Ar i.e. in Formulas I is 4- fluorophenyl.
The preparation method of the compound is：Lavo-ofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 Milliliter), 4- (4- fluorophenyl) thiosemicarbazides 0.7g, 3.8mmol shown in Formula VIII is added), back flow reaction 8 hours, mistake while hot Filter, solid are successively used ethanol washing 2 times, are distilled water washing 2 times, dry, with DMF- ethyl alcohol (V:V=5:3) mixed solvent is tied again Crystalline substance obtains pale yellow crystals object formula (I-6), obtains product 0.65g, m.p.236~238 DEG C.1H NMR (400MHz, DMSO-d6)： 11.77 (s, 1H, CH=N), 10.03 (s, 1H, NH), 9.13 (s, 1H, 2-H), 8.46 (s, 1H, NH), 7.82~7.47 (m, 5H, Ph-H and5-H), 4.63~4.34 (m, 3H, OCH2CH), 3.26 (t, 4H, piperazine-H), 2.51 (t, 4H, Piperazine-H), 2.25 (s, 3H, N-CH3), 1.47 (d, 3H, CH3)；MS(m/z)：Calcd.for C25H26F2N6O2S： 512.59[M]+；Found：513[M+H]+。
Embodiment 7
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- (4- chlorphenyl) thiosemicarbazides (I-7), chemical structural formula are：
Ar i.e. in Formulas I is the chloro- phenyl of 4-.
The preparation method of the compound is：Lavo-ofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 Milliliter), be added Formula VIII shown in 4- (4- chlorphenyl) thiosemicarbazides (0.7g, 3.5mmol), back flow reaction 10 hours, while hot Filtering, solid are successively used ethanol washing 2 times, are distilled water washing 2 times, dry, with DMF- ethyl alcohol (V:V=5:3) mixed solvent weight Crystallization, obtains pale yellow crystals object formula (I-7), obtains product 0.62g, m.p.216~218 DEG C.1H NMR (400MHz, DMSO-d6)： 11.78 (s, 1H, CH=N), 9.93 (s, 1H, NH), 8.91 (s, 1H, 2-H), 8.44 (s, 1H, NH), 7.86~7.46 (m, 5H, Ph-H and5-H), 4.62~4.35 (m, 3H, OCH2CH), 3.26 (t, 4H, piperazine-H), 2.46 (t, 4H, Piperazine-H), 2.24 (s, 3H, N-CH3), 1.46 (d, 3H, CH3)；MS(m/z)：Calcd.for C25H26ClFN6O2S： 529.04[M]+；Found：529[M+H]+。
Embodiment 8
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracts [4- (2,3,4- trifluorophenyl)] thiosemicarbazides (I-8), chemical structural formula are：
Ar i.e. in Formulas I is 2,3,4- trifluorophenyl.
The preparation method of the compound is：Lavo-ofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 Milliliter), be added Formula VIII shown in 4- (2,3,4- trifluorophenyl) thiosemicarbazides (0.8g, 3.6mmol), back flow reaction 8 hours, It filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol (V:V=5:3) it mixes molten Agent recrystallization, obtains pale yellow crystals object formula (I-8), obtains product 0.76g, m.p.243~245 DEG C.1H NMR (400MHz, DMSO- d6)：11.80 (s, 1H, CH=N), 10.06 (s, 1H, NH), 9.13 (s, 1H, 2-H), 8.47 (s, 1H, NH), 8.25~7.66 (m, 4H, Ph-Hand 5-H), 4.62~4.35 (m, 3H, OCH2CH), 3.26 (t, 4H, piperazine-H), 2.50 (t, 4H, Piperazine-H), 2.26 (s, 3H, N-CH3), 1.47 (d, 3H, CH3)；MS(m/z)：Calcd.for C25H24F4N6O2S： 548.57[M]+；Found：549[M+H]+。
Embodiment 9
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- (3- pyridyl group) thiosemicarbazides (I-9), chemical structural formula are：
Ar i.e. in Formulas I is 3- pyridyl group.
The preparation method of the compound is：Lavo-ofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 Milliliter), be added Formula VIII shown in 4- (3- pyridyl group) thiosemicarbazides (0.6g, 3.2mmol), back flow reaction 10 hours, while hot Filtering, solid are successively used ethanol washing 2 times, are distilled water washing 2 times, dry, with DMF- ethyl alcohol (V:V=5:3) mixed solvent weight Crystallization, obtains pale yellow crystals object formula (I-9), obtains product 0.50g, m.p.245~247 DEG C.1H NMR (400MHz, DMSO-d6)： 11.78 (s, 1H, CH=N), 10.10 (s, 1H, NH), 9.17 (s, 1H, 2-H), 8.88 (s, 1H, Py-H), 8.76 (d, 1H, Py- H), 8.46 (s, 1H, NH), 8.40~7.46 (m, 3H, Py-H and 5-H), 4.62~4.36 (m, 3H, OCH2CH), 3.26 (t, 4H, piperazine-H), 2.45 (t, 4H, piperazine-H), 2.25 (s, 3H, N-CH3), 1.47 (d, 3H, CH3)；MS (m/z)：Calcd.for C24H26FN7O2S：495.58[M]+；Found：496[M+H]+。
Embodiment 10
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- (2- furyl) thiosemicarbazides (I-10), chemical structural formula are：
Ar i.e. in Formulas I is 2- furyl.
The preparation method of the compound is：Lavo-ofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 Milliliter), it is added 4- (2- furyl) thiosemicarbazides (0.5g, 3.2mmol) shown in Formula VIII, back flow reaction 8 hours, mistake while hot Filter, solid are successively used ethanol washing 2 times, are distilled water washing 2 times, dry, with DMF- ethyl alcohol (V:V=5:3) mixed solvent is tied again Crystalline substance obtains pale yellow crystals object formula (I-10), obtains product 0.45g, m.p.242~244 DEG C.1H NMR (400MHz, DMSO-d6)： 11.76 (s, 1H, CH=N), 9.93 (s, 1H, NH), 9.05 (s, 1H, 2-H), 8.67 (d, 1H, Furan-H), 8.46 (s, 1H, NH), 7.83~7.26 (m, 3H, Furan-H and 5-H), 4.62~4.33 (m, 3H, OCH2CH), 3.25 (t, 4H, Piperazine-H), 2.45 (t, 4H, piperazine-H), 2.25 (s, 3H, N-CH3), 1.47 (d, 3H, CH3)；MS(m/z)： Calcd.forC23H25FN6O3S：484.56[M]+；Found：485[M+H]+。
Embodiment 11
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4- (2- thienyl) thiosemicarbazides (I-11), chemical structural formula are：
Ar i.e. in Formulas I is 2- thienyl.
The preparation method of the compound is：Lavo-ofloxacin aldehyde crude product (1.0g) shown in formula IV is dissolved in dehydrated alcohol (30 Milliliter), be added Formula VIII shown in 4- (2- thienyl) thiosemicarbazides (0.6g, 3.5mmol), back flow reaction 12 hours, while hot Filtering, solid are successively used ethanol washing 2 times, are distilled water washing 2 times, dry, with DMF- ethyl alcohol (V:V=5:3) mixed solvent weight Crystallization, obtains pale yellow crystals object formula (I-11), obtains product 0.53g, m.p.241~243 DEG C.1H NMR (400MHz, DMSO-d6)： 11.78 (s, 1H, CH=N), 9.92 (s, 1H, NH), 8.93 (s, 1H, 2-H), 8.46 (s, 1H, NH), 7.86~6.77 (m, 4H, Thiophen-Hand 5-H), 4.63~4.33 (m, 3H, OCH2CH), 3.26 (t, 4H, piperazine-H), 2.44 (t, 4H, Piperazine-H), 2.24 (s, 3H, N-CH3), 1.47 (d, 3H, CH3)；MS(m/z)：Calcd.for C23H25FN6O2S2： 500.62[M]+；Found：501[M+H]+。
Test example
The anti tumor activity in vitro of the lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives of embodiment 1-11 preparation Measurement
1, test sample
It is antitumor with lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives prepared by embodiment 1-11, and classics TOPO inhibitor 10-hydroxycamptothecine (Hydroxycamptothecin, HC) and lavo-ofloxacin (LOF) are test sample, totally 13 kinds, wherein HC It is control group with LOF, embodiment 1-11 sample is experimental group；
Experimental cancer cell line is respectively human liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell and human leukemia HL60 thin Born of the same parents' strain is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences.Normal cell uses VERO African green monkey kidney cell, and purchase is logical in Shanghai Growth Science and Technology Ltd..
2, measuring method
Measuring method the specific steps are：
1) it uses dimethyl sulfoxide (DMSO) to dissolve respectively above-mentioned 13 kinds of test samples first, is configured to 1.0 × 10- 2mol·L-1Then the stock solution of concentration uses the RPMI-1640 culture solution containing 10% (mass concentration) calf serum by stock solution Being diluted to has 5 concentration gradient (0.1,1.0,5.0,10.0,50.0 μm of olL-1) working solution；
2) the human liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell and human leukemia HL60 cell of logarithmic growth phase And VERO cell strain is then separately added into the dense with 5 of above-mentioned 13 kinds of samples with 6000, every hole cell inoculation in 96 orifice plates Spend the working solution of gradient.5gL is added in every hole after culture 48 hours–110 μ L of thiazolyl blue (MTT) solution, after continuing culture 4 hours Lauryl sodium sulfate (SDS) solution that 100 μ L mass concentrations 10% are added is further cultured for 24 hours, is then existed with microplate reader Respective absorbance (OD) value is measured at 570nm wavelength；
3) inhibiting rate of the test sample to cancer cell of various concentration is calculated by using the formula shown below,
Cancer inhibition rate=[(1- experimental group OD value)/control group OD value] × 100%,
Linear regression is finally made to the corresponding cancer inhibition rate of each concentration with the logarithm of each concentration of test sample, is obtained To dose-effect equation, each test sample is calculated to the half-inhibitory concentration of experiment cancer cell from gained dose-effect equation (IC50)；Each data are measured in parallel three times, are averaged, the results are shown in Table 1.
Anti-tumor activity (the IC of each test sample of table 150)
As it can be seen from table 1 the compound that embodiment 1-11 is provided is significantly stronger than the inhibitory activity of 3 kinds of cancer cells of experiment The activity of parent compound levofloxacin (LOF), especially phenyl ring are with F atom or heteroaromatic cycle compound to human pancreas cancer Activity, the IC suitable with the activity of control hydroxycamptothecin of Panc-1 cell50Value has reached micro-molar concentration.More meaningful It is that the compound that embodiment 1-11 is provided shows low toxicity VERO cell, shows that there is tumour cell relatively strong Selectivity, with druggability exploitation potentiality and value.It therefore, is first to carry out routine according to the general way of drug development Antitumor in-vitro screening, is then targetedly studied, thus the compound of the present invention have strong anti-tumor activity and compared with Low toxicity, can be by being mixed with anti-tumor drug with acid human-acceptable at salt or with pharmaceutical carrier.

Claims (5)

1. lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives, which is characterized in that specifically the compound of the following structure：
2. the preparation method of lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives described in claim 1, which is characterized in that Specifically comprise the following steps：
(1) lavo-ofloxacin shown in Formula II is subjected to hydrazinolysis with hydrazine hydrate and reacts lavo-ofloxacin acyl shown in obtained formula III Hydrazine；
(2) by lavo-ofloxacin hydrazides shown in formula III and the potassium ferricyanide in the ammonium hydroxide alkaline medium of chloroform normal-temperature reaction 8~ 12 hours, separate organic layer, and with saturated common salt water washing, anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, is made shown in formula IV Intermediate lavo-ofloxacin aldehyde crude product, be directly used in the next step；
(3) aromatic amine shown in Formula V and carbon disulfide are condensed as fragrant amino dithiocarbonic acid ammonium shown in Formula IV, then with chlorine Sodium acetate is condensed to yield S- carboxymethyl fragrant amino dithiocarbonic acid ester sodium salt shown in Formula VII, then replaces with hydrazine hydrate Reaction, it is post-treated to obtain 4- arylamino thiourea derivatives shown in Formula VIII；
Ar is as defined in claim 1 compound；
(4) by lavo-ofloxacin aldehyde crude product shown in formula IV with 4- arylamino thiourea derivatives shown in Formula VIII anhydrous Condensation reaction occurs in ethyl alcohol, can be prepared by lavo-ofloxacin aldehyde contracting 4- virtue described in claim 1 through processing after fully reacting Base thiosemicarbazides analog derivative.
3. the preparation method of lavo-ofloxacin aldehyde contracting 4- arylamino Thiourea analog derivative according to claim 2, special Sign is, in step (2), the molar ratio of lavo-ofloxacin hydrazides and the potassium ferricyanide shown in formula III is 1：3.0~5.0.
4. the answering in the preparation of antitumor drugs of lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives described in claim 1 With.
5. lavo-ofloxacin aldehyde contracting 4- arylamino thiourea derivatives are in the preparation of antitumor drugs according to claim 4 Application, which is characterized in that the anti-tumor drug be treat cancer of pancreas, liver cancer or leukaemia drug.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101643471A (en) * 2009-08-24 2010-02-10 河南大学 C3/C3 fluoroquinolone dimmer derivative using oxadiazole as connection chain as well as preparation method and application thereof
CN101648962A (en) * 2009-08-28 2010-02-17 河南大学 C3/C3 fluoroquinolone dipolymer derivative taking s-triazolo-[3,4-b][1,3,4] thiadiazole as connecting chain and preparation method and application thereof
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